Thrombotic microangiopathy (TMA) is a disease that is caused by injury to endothelial cells that results in thrombosis in capillaries and arterioles. One of the categories of thrombotic microangiopathy is complement-mediated. Complement-mediated thrombotic microangiopathy (CMTM) is also known as atypical hemolytic-uremic syndrome (aHUS), complement-mediated hemolytic uremic syndrome and thrombotic microangiopathies of unknown etiologies. aHUS occurs when the body's overactive complement system attacks the cells that line blood vessels in the kidneys, causing inflammation and the formation of abnormal clots. aHUS is a life threatening, progressive, genetic disease that is characterized by three major features: microangiopatic hemolytic anemia (MAHA), thrombocytopenia and kidney injury, which can lead to kidney damage, kidney failure and end-stage renal disease. In addition, a patient's central nervous system may become involved, and gastrointestinal symptoms may also be present.
Fifty percent of patients diagnosed with aHUS will die, develop end-stage renal disease or suffer permanent kidney injury within one year after diagnosis despite plasma exchange or plasma infusion therapy. aHUS is considered a rare disease (1 in 500,000 in the general population of the United States). However, some reports have cited a prevalence as high as 1 in 150,000 in certain pediatric populations.
Development of aHUS occurs through a combination of environmental and genetic factors. aHUS most frequently occurs following a triggering event such as organ transplantation, pregnancy, malignant hypertension, autoimmune disorders, sepsis, or malignancy. The genes associated with aHUS regulate the complement system, which provides the instructions for making proteins involved in the body's immune response. The proteins destroy bacteria and viruses, trigger inflammation, and remove debris from cells and tissues. The complement system must be carefully regulated so that it only targets unwanted material and does not attack the body's healthy cells. The regulatory proteins associated with aHUS protect healthy cells by preventing activation of the complement system when it is not needed.
Mutations in at least seven genes appear to be associated with an increase in the risk of developing aHUS. The most common genetic mutation is found in the complement factor H (CFH) gene. Other genes involved include the Membrane cofactor protein (CD46), Complement factor 1 (CF1), Complement component 3 (C3), Complement factor B (CFB), Complement factor H-related proteins including CFHR1, CFHR3, CFHR4, CFHR5, Thrombomodulin (THBD), Plasminogen (PLG), and Diacyl glycerol kinase (DGKE).
As a thrombotic microangiopathy, aHUS presents with clinical features that are nearly identical to thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, making immediate laboratory differentiation essential.
Current genetic methods for confirming a clinical diagnoses of CMTM or aHUS takes at least 28 days. However, since aHUS is a progressive disease, a faster turnaround time is required for faster patient diagnosis and management.
Therefore, there is a need for an improved method to rapidly identify mutations, polymorphisms and other variants of genes involved with CMTM in order to identify, diagnosis, and assess the risk of an individual in developing CMTM.